Role of estrogen receptors in pancreatic beta-cell survival and insulin secretion

在糖尿病中，胰腺中产生胰岛素的胰岛β细胞因凋亡而死亡，导致胰岛素依赖。然而， 促进β-细胞死亡的机制仍然没有完全弄清楚。为了开发新型有效的糖尿病疗法，增加我们对调节β细胞存活过程的基本知识至关重要 患者有证据表明，女性激素，17 β-雌二醇（雌二醇），保护胰岛素的生产和预防糖尿病。虽然雌二醇主要通过两种不同的雌激素受体起作用， (ERs)最近，G蛋白偶联雌激素受体（GPER），也被称为GPR 30，已被认为是雌激素的假定膜受体，其介导一系列的雌激素受体调节。 非基因组E2信号。这些ER在保护胰岛细胞存活方面的单独贡献尚未确定。我们的目的是为这个探索性的应用程序是阐明的贡献， 通过使用遗传小鼠模型，通过GPER在体内β细胞存活中的非经典雌激素作用。我们将使用联合的β细胞特异性ER α/ER β缺陷小鼠（β ERabKO）和GPER缺陷小鼠.使用这些工具，结合药理学探针，我们将研究GPER作用在体内和培养的胰岛中β细胞存活中的作用。通过拟议的研究-这是第一次调查快速，非基因组ER在体内的肿瘤细胞存活-我们计划证明GPER是重要的肿瘤细胞存活在体内，因此代表了一个可行的治疗干预的目标。

In diabetes, the death of insulin-producing ß-cells in the pancreas by apoptosis leads to insulin dependence. Yet, the events that promote ß-cell death are still not fully understood. It is essential to increase our basic knowledge of the processes regulating beta-cell survival in order to develop novel and efficient therapies for diabetic patients. Evidence suggests that the female hormone, 17 ß-estradiol (estradiol), protects insulin production and prevents diabetes. Although estradiol acts primarily via two distinct estrogen receptors (ERs), ERalpha and ERbeta, recently, the G protein-coupled estrogen receptor (GPER), also called GPR30 has been recognized as a putative membrane receptor for estrogens that mediates a series of non-genomic E2 signals. The individual contributions of these ERs in protecting ß-cell survival have not been established. Our objective for this exploratory application is to elucidate the contribution played by non-classical estrogen actions via GPER in ß-cell survival in vivo, through the use of genetic mouse models. We will use a combined ß-cell specific ERalpha/ERbeta deficient mouse (ßERabKO) and a GPER deficient mouse. Using these tools, in combination with pharmacological probes, we will study the role of GPER actions in beta-cell survival in vivo and in cultured islet. Through the proposed research - which is the first investigation of rapid, non genomic ERs in ß-cell survival in vivo - we plan to demonstrate that GPER is important to ß-cell survival in vivo, and therefore represent a viable targets for therapeutic intervention.